Method for detecting an analyte in blood

ABSTRACT

The methods and apparatus for detecting an analyte in blood are useful for detecting an analyte in tissue of a subject. The apparatus comprises a sensor, which comprises an elongated conductive material having a protrudent end, the protrudent end comprising an electrode that detects the presence of an analyte; a substrate affixed to the conductive material; and a support having an external surface, a proximal end, and a distal end. The conductive material is positioned on the support and the protrudent end of the conductive material protrudes beyond the distal end of the support. Optionally, the sensor is suspended within the lumen of a venous flow device. Typically, only a portion of the sensor is suspended within the lumen of the venous flow device, said portion comprising the protrudent end of the conductive material. Alternatively, the conductive material is positioned on the external surface of the intravenous infusion catheter.

This application is a continuation of U.S. patent application Ser. No.11/348,894, filed Feb. 7, 2006, which is a continuation-in-part of U.S.patent application Ser. No. 10/935,954, filed Sep. 8, 2004, now U.S.Pat. No. 7,468,033, issued Dec. 23, 2008, the entire contents of whichare incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

This invention relates generally to the manufacture and use of a sensorsuitable for direct contact with blood, interstitial tissue or othermedium. The sensor is capable of measuring glucose and/or otheranalytes, the design of the sensor facilitating introduction and use ofthe sensor in a variety of environments, including blood vessels,extracorporeal circuits, and interstitium.

BACKGROUND OF THE INVENTION

The assay of biochemical analytes such as glucose and lactate isimportant in a variety of clinical contexts. Biomedical sensors, such asenzyme electrodes, can be used to determine the concentration of certainbiochemicals rapidly and with considerable accuracy. Enzyme electrodescan detect glucose, urea, uric acid, various alcohols, and a number ofamino acids under certain well-defined conditions. For example, themonitoring of glucose concentrations in fluids of the human body is ofparticular relevance to diabetes management. Continuously orintermittently operating glucose sensors, including sensors implanted inthe human body (such as the Continuous Glucose Monitoring System (CGMS)and Telemetered Glucose Monitoring System (TGMS) by Medtronic MiniMed),are sought for the management of diabetes, for example, for warning ofimminent or actual hypoglycemia as well as its avoidance. The monitoringof lactate concentrations in fluids of the human body is useful in thediagnosis and assessment of a number of medical conditions includingtrauma, myocardial infarction, congestive heart failure, pulmonary edemaand septicemia. For example, glucose sensors suitable for in vivo usecan be prepared by depositing a glucose sensitive enzyme, such asglucose oxidase, onto an electrode via an electromotive plating process.

Biomedical measuring devices commonly used to monitor physiologicalvariables include amperometric sensor devices that utilize electrodesmodified with an appropriate enzyme coating. Sensors having such enzymeelectrodes enable the user to determine the concentration of variousanalytes rapidly and with considerable accuracy, for example byutilizing the reaction of an enzyme and an analyte where this reactionutilizes a detectable coreactant and/or produces a detectable reactionproduct. For example, a number of glucose sensors have been developedthat are based on the reaction between glucose and glucose oxidase(GOx). As glucose and oxygen diffuse into an immobilized enzyme layer ona sensor, the glucose reacts with oxygen and water to produce H₂O₂.Glucose can be detected electrochemically using the immobilized enzymeglucose oxidase coupled to oxygen and/or hydrogen peroxide-sensitiveelectrodes. The reaction results in a reduction in oxygen and theproduction of hydrogen peroxide proportional to the concentration ofglucose in the sample medium. A typical device is composed of at leasttwo detecting electrodes, or at least one detecting electrode and areference signal source, to sense the concentration of oxygen orhydrogen peroxide in the presence and absence of enzyme reaction.Additionally, the complete monitoring system typically contains anelectronic sensing and control means for determining the difference inthe concentration of the substances of interest. From this difference,the concentration of analytes such as glucose can be determined.

A wide variety of such analyte sensors as well as methods for making andusing such sensors are known in the art. Examples of such sensors,sensor sets and methods for their production are described, for example,in U.S. Pat. Nos. 5,390,691, 5,391, 250, 5,482,473, 5,299,571, 5,568,806as well as PCT International Publication Numbers WO 01/58348, WO03/034902, WO 03/035117, WO 03/035891, WO 03/023388, WO 03/022128, WO03/022352, WO 03/023708, WO 03/036255, WO03/036310 and WO 03/074107, thecontents of each of which are incorporated herein by reference. While anumber of sensor designs and processes for making such sensors are knownin the art, many are tailored to subcutaneous applications. Thereremains a need for the identification of the methods and processes thatfacilitate the measurement of glucose and other analytes in a variety ofdirect blood contacting applications. The present invention fulfillsthese needs and provides further related advantages.

SUMMARY OF THE INVENTION

To overcome the limitations in the prior art described above, and toovercome other limitations that will become apparent upon reading andunderstanding the present specification, embodiments of the inventionprovide methods and apparatus for detecting an analyte in blood. Theinvention provides an apparatus that comprises a sensor for detecting ananalyte in tissue of a subject. The sensor comprises an elongatedconductive material having a protrudent end, the protrudent endcomprising an electrode that detects the presence of an analyte; asubstrate affixed to the conductive material; and, optionally, a supporthaving an external surface, a proximal end, and a distal end. Theconductive material is positioned on the support and the protrudent endof the conductive material protrudes beyond the distal end of thesupport.

In one embodiment, the substrate comprises a polyimide film that isabout 0.005 to about 0.007 inch in thickness. In this embodiment, thesubstrate is sufficiently supportive that a separate support element isnot necessary. The entire sensor is therefore capable of protruding intothe sensor environment where it can contact the analyte to be detected.The substrate optionally comprises an insulative layer that covers theconductive material and does not cover the electrode. In one embodiment,the apparatus further comprises an assembly means having a sensor endand an exterior face, wherein the sensor is affixed to the sensor end ofthe assembly means, and the assembly means is adapted for coupling witha venous flow device.

In a typical embodiment, the apparatus further comprises a venous flowdevice coupled to the assembly means, the venous flow device having alumen, wherein the sensor is suspended within the lumen of the venousflow device. Optionally, only a portion of the sensor is suspendedwithin the lumen of the venous flow device, said portion comprising theprotrudent end of the conductive material.

In one embodiment, the support comprises an intravenous infusioncatheter having a lumen. The intravenous catheter can have a singlelumen or more than one lumen. The conductive material can be positionedon the external surface of the intravenous infusion catheter, and/or onthe lumen of the intravenous infusion catheter.

In one embodiment, the venous flow device comprises an external bloodloop. The external blood loop can optionally further comprise a septumadapted to receive injections.

Typically, the sensor comprises an enzymatic, molecular recognition,optochemical or electrochemical sensor, such as a glucose sensor.

The substrate can comprise a hydrophilic material. Examples ofhydrophilic materials include, but are not limited to, polyurethane,acrylate, polyester and cross-linked PEO. In one embodiment, the sensorfurther comprises a coating.

In one embodiment, the distal end of the sensor is coated with ahydrophilic material. Typically, the distal end is dip-coated with thehydrophilic material. Alternatively, the coating can be applied bypainting, spraying or other means known in the art. The sensor can becoated with a medicinal agent, such as an anticoagulant, or anantimicrobial agent. In one embodiment, the coating contains ahydrophilic polymer. Examples of hydrophilic polymers include, but arenot limited to, polyhydroxyethylmethacrylate (PHEMA), polysaccharide,polyacrylamide, polyurea, polyethylene oxide (PEO) containingpolyurethane, PEO containing polyurea and cross-linked PEO. Optionally,the coating comprises a stiffening agent.

The apparatus can comprise a sensor that detects the presence of ananalyte and an assembly means. The assembly means has a sensor end,wherein the sensor end of the assembly means is affixed to the sensor,and the assembly means is adapted for coupling with a venous flowdevice. By coupling with a venous flow device, the assembly means bringsthe sensor into direct contact with blood flowing through the venousflow device.

In some embodiments, the apparatus further comprises a venous flowdevice coupled to the assembly means. The venous flow device has alumen, and the sensor is positioned as desired, relative to the lumen ofthe venous flow device. In one embodiment, the sensor extends fromwithin the lumen of the venous flow device beyond a distal end of thevenous flow device. In another embodiment, the sensor is positionedexternal to the venous flow device and therefore does not pass throughthe lumen of the venous flow device. The venous flow device can be anintravenous catheter, such as a peripheral catheter, central catheter,or peripherally-inserted central catheter. In some embodiments, thevenous flow device comprises an external blood loop, such as is used inextra-corporeal membrane oxygenation or hemodialysis. The venous flowdevice can have one or more lumens. Optionally, an opening is providedbetween the lumens. An inter-lumenal opening can permit the introductionof a medication, such as an anti-coagulant, into the area in which thesensor is suspended. Placement of the opening or openings can bedesigned to direct a medication or other agent to a particular portionor region of the sensor.

In some embodiments, the venous flow device further comprises a septumadapted to receive injections. For use with an external blood loop, theseptum can be affixed to a T-connector, for example, so that a sensorapparatus can be introduced into the external blood loop through theseptum. In another embodiment, the external blood loop further comprisesa cross connector adapted to receive injections from opposing sides ofthe external blood loop.

In some embodiments of the apparatus, the assembly means furthercomprises an alignment means adapted to guide insertion of the sensorinto a venous flow device. For example, the alignment means can comprisea needle having a lumen, or other piercing device. The piercing devicecan be fixed or removable, and optionally, includes a slot or othermeans to allow removal of the piercing device without removing thesensor. The sensor shape can also be modified to facilitate removal ofthe piercing device without disturbing the sensor position.

In a typical embodiment, the assembly means comprises a lure lockconnector, of either the fixed or rotating variety. Variations on a lurelock, or a custom cap or housing can serve as an assembly means,providing a means for introducing the sensor into the area of blood flowwhile protecting the integrity of the venous flow. The assembly meanscan be designed to clip into place for secure and accurate positioning.A clip can be used to attach and/or release the apparatus to/from thevenous flow device.

The apparatus can further comprise a medication delivery system, whereinthe medication delivery system comprises means for infusing a medicationinto the venous flow device. In addition, the apparatus can include afeedback loop, wherein an output from the sensor is communicated to themedication delivery system. In such a closed loop system, sensor outputcan control infusion of medication, such as insulin and/or glucose, orother desired medication whose dosage would be adjusted on the basis ofsensor-gathered information.

The sensor can be any biocompatible sensor, suitable for short orlong-term use. In preferred embodiments, the sensor is an optical,optochemical, molecular recognition, enzymatic or electrochemicalsensor. One example of a sensor includes a glucose sensor.

In some embodiments, the sensor is operatively coupled to a monitor orother device. The coupling can be direct or telemetric, and facilitatescontinuous or regular monitoring of the subject's analyte levels. Forexample, in a hospital setting, the apparatus can be used to monitor apatient's glucose or other analyte level from a remote location, such asa nursing station.

The invention additionally provides a method of introducing a sensorinto the circulating blood of a subject. The method comprises contactinga venous flow device with the circulating blood of the subject andintroducing an apparatus of the invention into the venous flow device.The sensor contacts the circulating blood of the subject as the bloodflows through the venous flow device. In one embodiment, the venous flowdevice comprises an external blood loop having a port adapted to receivethe apparatus. Optionally, the external blood loop further comprises asecond port adapted to receive an alignment means. The method canfurther comprise introducing an alignment means into the external bloodloop from a side opposing the port adapted to receive the apparatusprior to introducing the apparatus.

In one embodiment, the method further comprises introducing an alignmentmeans into the port prior to or simultaneously with introduction of theapparatus. The alignment means can be removed following introduction ofthe apparatus. Alternatively, the venous flow device can be a catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates an external blood loop 10 containing a T-connector12 and an apparatus 14 of the invention wherein the sensor 16 protrudesinto the blood loop 10 upon connection of the assembly means 14 to theT-connector 12 via a lure lock 18.

FIG. 1B shows how the sensor 16 extends from the sensor end 20 of theassembly means 14 and how the assembly means 14 is adapted for couplingwith the T-connector 12 of the blood loop 10.

FIG. 2 illustrates an alternative embodiment of the assembly means 14that incorporates a T-connector 12 and has been plumbed into theexternal blood circuit 10. In this configuration, the sensor (notvisible in this view) orientation is perpendicular to the blood flowthrough the circuit 10.

FIG. 3A illustrates a variation on the embodiment shown in FIG. 2,wherein the sensor (not visible in this view) enters the circuit 10 atan angle, with an orientation that is more parallel to the flow ofblood. A portion of the assembly means 14 is excluded from this view tomore clearly illustrate the entrance of the sensor into the bloodcircuit.

FIG. 3B completes the illustration of FIG. 3A by including the remainderof the assembly means 14.

FIG. 4A illustrates a cross-connector 40 capable of insertion in anexternal blood circuit. The cross-connector 40 provides two injectionsites 42, 44 opposing one another. A piercing device 46 is introducedthrough the first injection site 44 and exits from the second injectionsite 42, providing a guide for insertion of the sensor 16 through thesecond injection site 42. The assembly means 14 includes guides 48 tofacilitate alignment of the sensor 16 during insertion.

FIG. 4B shows the embodiment of FIG. 4A after the piercing device 46 haspassed through both injection sites 42, 44, exposing a guide 46 forsensor 16 insertion.

FIG. 4C shows the embodiment of FIGS. 4A and 4B after the sensor 16 hasbeen positioned in the cross connector of the blood circuit 40 and thepiercing device 46 removed.

FIG. 5A illustrates an introducer catheter 50 used to introduce thesensor 16 into the circuit 10 via a T-connector 12.

FIG. 5B shows the embodiment of FIG. 5A after the introducer catheter 50has been inserted and the sensor 16 is being introduced into the circuit10.

FIG. 5C shows the sensor 16 in position, with its distal tip 52positioned perpendicular to the flow of blood through the connector 12.

FIG. 6A illustrates an assembly means 14 that includes a piercing device50 for introducing the sensor (not visible in this view) into a venousflow device 10, e.g., via a septum 60.

FIG. 6B shows the assembly means 14 of FIG. 6A after it has beeninserted into the venous flow device 10.

FIG. 7A illustrates an assembly means 14 that includes, in addition to apiercing device 50, a clip 70 that can be activated for attachment to orrelease from the venous flow device (not visible in this view), andwhich further guides accurate placement of the sensor (not visible inthis view).

FIG. 7B shows the embodiment of FIG. 7A as it is being introduced intothe circuit 10.

FIG. 7C shows the sensor 50 in position, with its distal tip 52positioned perpendicular to the flow of blood through the venous flowdevice 10.

FIG. 8A illustrates a cross-sectional view of a needle 50, or piercingdevice 50, modified to include a slot 82 to facilitate removal afterintroduction of the sensor (not visible in this view).

FIG. 8B shows a sensor 16 for use with the piercing device 50 of FIG.8A, which sensor 16 has a jog 80 along its length to permit removal ofthe piercing device 50 while leaving the sensor 16 in place.

FIG. 8C shows the sensor 16 of FIG. 8B inside the slot 82 of thepiercing device 50 shown in FIG. 8A.

FIG. 8D shows the sensor 16 and piercing device 50 of FIG. 8C, with thepiercing device 50 separated from the sensor 16.

FIG. 9A illustrates an assembly means 14 adapted for coupling to anintravenous catheter 90 via a lure lock 18.

FIG. 9B shows the embodiment of FIG. 9A after insertion of the sensor 16into the catheter 90.

FIG. 9C shows a variation on the embodiment of FIG. 9B.

FIGS. 10A-10C illustrate various embodiments of an assembly means 14that includes a side port 92 and is coupled to an intravenous catheter90.

FIG. 11A is a block diagram of a characteristic monitor embodiment thatcan be used with the present invention.

FIG. 11B is a block diagram of a telemetered characteristic monitorembodiment that can be used with the present invention.

FIGS. 12A-C illustrate 3 embodiments of the apparatus. In FIG. 12A, thesupport 300 is a catheter and the conductive material 302 protrudes fromthe lumen 304 of the catheter. In FIG. 12B, the conductive material 302is affixed to the external surface 310 of the catheter 300 and protrudesbeyond the distal end 306 of the catheter 300. In FIG. 12C, thefunctions of the support 300 and substrate 308 are conflated, such thatonly the conductive material 302 and the substrate (e.g., a 0.005-0.007inch thick polyimide tape) 308 are necessary. In this latter embodiment,the conductive material 302 protrudes laterally with respect to thedistal end 306.

DETAILED DESCRIPTION

All scientific and technical terms used in this application havemeanings commonly used in the art unless otherwise specified. As used inthis application, the following words or phrases have the meaningsspecified.

As used herein, the “sensor end” of the assembly means refers to theportion of surface of the assembly means that is enclosed when theassembly means is coupled to a venous flow device. The sensor is affixedto the sensor end of the assembly means and is positioned within thevenous flow device upon coupling of the assembly means to a venous flowdevice.

As used herein, the “exterior face” of the assembly means refers to theportion of surface of the assembly means that remains exposed when theassembly means is coupled to a venous flow device.

As used herein, “affixed to” means attached to, stuck to, against orfused with such that a substance affixed to an object remainssubstantially attached to or closely associated with the object. In oneexample of a substrate affixed to a conductive material, the substrateand conductive material are fabricated as a single element, which canthen be positioned on a support.

As used herein, “hydrophilic material” means a material having a strongtendency to bind or absorb water, which is sufficient to result inswelling and formation of gels. This property is characteristic of somenatural polymers, including carbohydrates, proteins and man-madepolymers (e.g., hydrogels).

As used herein, “a” or “an” means at least one, and unless clearlyindicated otherwise, includes a plurality.

Overview

The invention provides methods and apparatus for detecting an analyte intissue, typically blood. The apparatus is particularly suited for usesthat involve bringing a sensor into direct contact with blood in vivo orin an extracorporeal circuit. The apparatus comprises a sensor thatdetects the presence of an analyte and, optionally, a support and/or anassembly means. The sensor comprises an elongated conductive materialhaving a protrudent end, the protrudent end comprising an electrode thatdetects the presence of an analyte; a substrate affixed to theconductive material; and, in some embodiments, a support having anexternal surface, a proximal end, and a distal end. The conductivematerial is positioned on the support and the protrudent end of theconductive material protrudes beyond the distal end of the support.

The assembly means has a sensor end, wherein the sensor end of theassembly means is affixed to the sensor, and the assembly means isadapted for coupling with a venous flow device. By coupling with avenous flow device, the assembly means brings the sensor into directcontact with blood flowing through the venous flow device. Examples ofvenous flow devices that bring the sensor into direct contact with theblood of a subject include, but are not limited to, intravenouscatheters and external blood loops, such as are used in extra corporealmembrane oxygenation or hemodialysis.

Sensor

The sensor can be any biocompatible sensor, suitable for short orlong-term use. In preferred embodiments, the sensor is an optical,optochemical, molecular recognition, enzymatic or electrochemicalsensor. One example of a sensor includes a glucose sensor. The sensormay also measure, in addition to, or in lieu of blood glucoseconcentration, the concentration of oxygen, potassium, hydrogenpotential (pH), lactate, one or more minerals, analytes, chemicals,proteins, molecules, vitamins, and the like, and/or other physicalcharacteristics such as temperature, pulse rate, respiratory rate,pressure, and the like.

An exemplary sensor includes a working electrode plated with an enzyme.A sensor can have a reference electrode, a working electrode, and acounter electrode deposited on a polymeric sheet or other substrate. Thesensor further includes a series of bonding pads. The entire electrodearray can then be coated with a layer of a polymer. The electrodes canbe made of any conductive surface, e.g., gold, platinum, palladium,chromium, copper, aluminum, pyrolitic carbon, composite material (e.g.,metal-polymer blend), nickel, zinc, titanium, or an alloy, such ascobalt-nickel-chromium, or titanium-aluminum-vanadium, which isdeposited on any of a variety of suitable materials, including glass,polyimide or polyester. In some embodiments, the electrode arrayincludes a flex-circuit layout/design. Of course, those skilled in theart will recognize that variations of the above components, and othertypes of electrodes can be used in the invention. The sensor can becoated further with a hydrophilic polymer, which provides for reductionof biofouling and enhanced sensor performance in a biologicalenvironment.

The sensor comprises an elongated conductive material having aprotrudent end, the protrudent end comprising an electrode that detectsthe presence of an analyte; a substrate affixed to the conductivematerial; and a support having an external surface, a proximal end, anda distal end. The conductive material is positioned on the support andthe protrudent end of the conductive material protrudes beyond thedistal end of the support. In a typical embodiment, the protrudent endprotrudes longitudinally beyond the distal end (e.g., as shown in FIG.12A-12B). Alternatively, such an embodiment in which the substrate andsupport functions are conflated, the protrudent end may protrudelaterally from the distal end (e.g., as shown in FIG. 12C). Thesubstrate optionally comprises an insulative layer that covers theconductive material and does not cover the most distal portion where theelectrode makes contact with and detects the analyte.

In a typical embodiment, the sensor comprises a thin film vascularsensor such as described in U.S. Pat. Nos. 5,497,772, 5,660,163,5,750,926, 5,791,344, 5,917,346, 5,999,848, 5,999,849, 6,043,437,6,081,736, 6,088,608, 6,119,028, 6,259,937, 6,472,122, and 6,671,554,and U.S. patent application Ser. Nos. 10/034,627 (published as U.S.patent publication no. 2003/0078560 A1, Apr. 24, 2003), Ser. No.10/331,186 (published as U.S. patent publication no. 2004/0061232 A1,Apr. 1, 2004), Ser. No. 10/671,996 (published as U.S. patent publicationno. 2004/0061234 A1, Apr. 1, 2004), Ser. No. 10/335,574 (published asU.S. patent publication no. 2004/0064156 A1, Apr. 1, 2004), Ser. No.10/334,686 (published as U.S. patent publication no. 2004/0064133 A1,Apr. 1, 2004), and Ser. No. 10/365,279 (published as U.S. patentpublication no. 2003/0220552 A1, Nov. 27, 2003), which are hereinincorporated by reference.

In some embodiments, the biosensor is an optical affinity sensor, e.g.,having a glucose binding site. The sensor, which includes a reflectivesubstrate, can be coated with a hydrophilic, biocompatible and glucosepermeable coating. Optical sensors for detection of analytes aredescribed in U.S. Pat. Nos. 6,256,522, and 5,143,066.

Other examples of sensors are described in U.S. Pat. Nos. 4,671,288(electrochemical sensor); U.S. Pat. No. 5,320,725 (amperometric sensor);U.S. Pat. No. 5,403,700 (polyimide-based sensor design); and U.S. Pat.No. 5,540,828 (sensor with a polymer-modified surface). Those skilled inthe art can readily appreciate the ability to adapt the teachings of thepresent invention to a variety of known sensor types and configurations.

A preferred sensor for use with the invention comprises a thin film,such as a Kapton® sheet (DuPont), affixed to a rigid substrate, such asglass. A fabrication method for producing thin film electrochemicalsensors is described in U.S. Pat. No. 5,391,250. By this method, one ormore sensors are formed on a rigid flat substrate, such as a glassplate. The sensors are formed in a manner compatible withphotolithographic mask and etch techniques, but wherein the sensors arenot physically adhered or attached directly to the substrate.Accordingly, finished sensors can be removed quickly and easily from thesubstrate by simple lift-off separation.

In one embodiment, a thick film is used. For example, rather than a0.001 inch thin film, the film is several-fold thicker, typically about0.005 to about 0.007 inch. In this embodiment, the substrate comprises apolyimide film that is about 0.005 to about 0.007 inch in thickness. Inthis latter embodiment, the substrate serves as the support due to thesubstantial support provided by the polyimide film (FIG. 12C). Aseparate element for support is not necessary, although could be addedif desired, such as a catheter for delivery of other substance(s) to thesite. As with the thin film, the thick film can comprise a conventionalmaterial, such as a Kapton® sheet (DuPont). Those of skill in the artunderstand that a range of thicknesses are possible for the substratecomprising a polyimide film. In certain embodiments of the invention,the film is about 0.1, to about 0.125, 0.15, 0.175 or 0.2 millimeters inthickness.

The conductive material can be surrounded or encompassed by the supportor be positioned on the support. In addition to adding rigidity andstrength to the sensor, the support can create an improved seal, forexample, upon insertion into a septum. Positioning the conductivematerial inside the lumen of a cylindrical or tubular support, as shownin FIG. 12A, can improve the sealing. The exterior surface of the tubeprovides a nice, smooth, round surface to seal against. The interior,e.g., around the conductive material, can be sealed with silicone or UVcurable sealant. In other embodiments, such as shown in FIG. 12B-12C,the conductive material is positioned on the external surface of thesupport. Those skilled in the art will appreciate variations on theshape and configuration of the support that can be tailored toparticular objectives.

Each sensor comprises a plurality of elongated thin film conductorsformed between an underlying insulative thin film base layer and anoverlying insulative thin film cover layer. Apertures are formed in thecover layer to expose distal end electrodes and proximal end contactpads. In a glucose monitoring application, the thin film sensor isplaced so that the distal end electrodes are in direct contact withpatient blood, and wherein contact pads are disposed externally forconvenient connection to a monitoring device.

The substrate comprises a rigid and flat structure suitable for use inphotolithographic mask and etch processes. In this regard, the substratedefines an upper surface having a high degree of uniform flatness. Apolished glass plate may be used defining the smooth upper surface.Alternative substrate materials include, for example, stainless steel,aluminum, and plastic materials such as Delrin, etc. In someembodiments, complete rigidity of the substrate is not desired, as someflexibility may be desired for insertion into a blood vessel,particularly for sensors of extended length (e.g., for use with a 22gauge intravenous infusion catheter). In such an embodiment, sufficientrigidity is provided at the distal end to facilitate electrodemanufacture, but the bulk of the sensor length is sufficiently flexibleto permit threading of the sensor through venous flow devices or bloodvessels.

A thin layer film of a curable adhesive, provided as shown in the formof a die-cut strip or frame, is applied in a closed loop pattern to theperimeter of the substrate. The base layer is then placed on thesubstrate, with a perimeter of the base layer in intimate seated contactupon the adhesive strip. The thus-assembled components define a shallowcavity between a central portion of the base layer and the underlyingsubstrate, with the adhesive strip circumscribing the peripheral edge ofthe cavity. In one embodiment, the base layer comprises a thin filmsheet of insulative material, such as polyimide having a film thicknesson the order of about 0.003 inch. The adhesive strip comprises an epoxyresin, which may be impregnated with fiberglass, such as an epoxy resinavailable from 3M Aerospace Division of Springfield, Mo., under the nameAF-163-205T. Alternative adhesive materials may include ultravioletcurable adhesives, etc. Moreover, if desired for improved adhesionbetween the base layer and the adhesive strip, a perimeter region of thebase layer may be surface etched.

In one embodiment, the sensor further comprises a coating. The sensorcan be coated with a medicinal agent, such as an anticoagulant, or anantimicrobial agent. In one embodiment, the coating contains ahydrophilic polymer. Examples of hydrophilic polymers include, but arenot limited to, polyhydroxyethylmethacrylate (PHEMA), polysaccharide,polyacrylamide, polyurea, polyethylene oxide (PEO) containingpolyurethane, PEO containing polyurea and cross-linked PEO. Optionally,the coating comprises a stiffening agent.

Sensors of the invention can also be incorporated into a wide variety ofmedical systems known in the art. Sensors of the invention can be usedfor example in a closed loop infusion systems designed to control therate that medication is infused into the body of a user. Such a closedloop infusion system can include a sensor and an associated meter, whichgenerates an input to a controller, which in turn operates a deliverysystem (e.g. one that calculates a dose to be delivered by a medicationinfusion pump). In such contexts, the meter associated with the sensormay also transmit commands to, and be used to remotely control, thedelivery system. Illustrative systems are disclosed for example in U.S.Pat. Nos. 6,558,351 and 6,551,276; PCT Application Nos. US99/21703 andUS99/22993; as well as WO 2004/008956 and WO 2004/009161, all of whichare incorporated herein by reference.

In general, the analyte sensor apparatus structure comprises a baselayer (substrate) and a conductive layer disposed upon the base layerthat includes one or more electrodes. For example, the conductive layercan include a working electrode, a reference electrode and/or a counterelectrode. These electrodes can be spaced in proximity, or alternativelyare spaced distally according to the preferred design. The sensorapparatus design is such that certain electrodes (e.g. the workingelectrode) can be exposed to the blood, containing the analyte to besensed in the sensor apparatus. The sensor apparatus design is such thatcertain electrodes (e.g. the reference electrode) are not exposed to theblood to be analyzed.

Typically, the analyte sensor apparatus includes an analyte sensinglayer disposed on the conductive layer, typically covering a portion orall of the working electrode. This analyte sensing layer detectablyalters the electrical current at the working electrode in the conductivelayer in the presence of an analyte to be sensed. As disclosed herein,this analyte sensing layer typically includes an enzyme or antibodymolecule or the like that reacts with the analyte of interest in amanner that changes the concentrations of a molecule that can modulatethe current at the working electrode. Illustrative analyte sensinglayers comprise an enzyme such as glucose oxidase (e.g. for use inglucose sensors) or lactate oxidase (e.g. for use in lactate sensors).Typically, the analyte sensing layer further comprises a carrier proteinin a substantially fixed ratio with the analyte sensing compound (e.g.the enzyme) and the analyte sensing compound and the carrier protein aredistributed in a substantially uniform manner throughout the analytesensing layer.

Optionally, the analyte sensing layer has a protein layer disposedthereon and which is typically between the analyte sensing layer and ananalyte modulating layer. A protein within the protein layer can be analbumin such as bovine serum albumin or human serum albumin. Typicallythis protein is cross-linked. Without being bound by a specificscientific theory, it is believed that this separate protein layerenhances sensor function and provides surprising functional benefits byacting as a capacitor that diminishes sensor noise (e.g. spuriousbackground signals). For example, in the sensors of the invention, someamount of moisture may form under the analyte modulating membrane layerof the sensor, the layer which regulates the amount of analyte that cancontact the enzyme of the analyte sensing layer. This moisture maycreate a compressible layer that shifts within the sensor as a patientusing the sensor moves. Such shifting of layers within the sensor mayalter the way that an analyte such as glucose moves through the analytesensing layers in a manner that is independent of actual physiologicalanalyte concentrations, thereby generating noise. In this context, theprotein layer may act as a capacitor by protecting an enzyme fromcontacting the moisture layer. This protein layer may confer a number ofadditional advantages such as promoting the adhesion between the analytesensing layer and the analyte modulating membrane layer. Alternatively,the presence of this layer may result in a greater diffusion path formolecules such as hydrogen peroxide, thereby localizing it to theelectrode sensing element and contributing to an enhanced sensorsensitivity.

Typically, the analyte sensing layer and/or the protein layer disposedon the analyte sensing layer has an adhesion promoting layer disposedthereon. Such adhesion promoting layers promote the adhesion between theanalyte sensing layer and a proximal layer, typically an analytemodulating layer. This adhesion promoting layer preferably comprises asilane compound such as γ-aminopropyltrimethoxysilane which is selectedfor its ability to promote optimized adhesion between the various sensorlayers and functions to stabilize the sensor. Interestingly, sensorshaving such a silane containing adhesion promoting layer exhibitunexpected properties, including an enhanced overall stability. Inaddition, silane containing adhesion promoting layers provide a numberof advantageous characteristics in addition to an ability to enhancingsensor stability and can for example play a beneficial role ininterference rejection as well as in controlling the mass transfer ofone or more desired analytes.

In some embodiments of the invention, the adhesion promoting layerfurther comprises one or more compounds that can also be present in anadjacent layer, such as the polydimethyl siloxane (PDMS) compounds, thatlimit the diffusion of analytes such as glucose through the analytemodulating layer. The addition of PDMS to the adhesion promoting layer,for example, can be advantageous in contexts where it diminishes thepossibility of holes or gaps occurring in the AP layer as the sensor ismanufactured.

Typically the adhesion promoting layer has an analyte modulating layerdisposed thereon which modulates the diffusion of analytes therethrough.The analyte modulating layer can include compositions (e.g. polymers andthe like) that enhance the diffusion of analytes (e.g. oxygen) throughthe sensor layers and consequently enrich analyte concentrations in theanalyte sensing layer and/or compositions that limit the diffusion ofanalytes (e.g. glucose) through the sensor layers and consequently limitanalyte concentrations in the analyte sensing layer. An illustrativeexample of this is a hydrophilic glucose limiting membrane (i.e. thatlimits the diffusion of glucose therethrough) comprising a polymer suchas polydimethyl siloxane or the like.

Typically the analyte modulating layer further comprises one or morecover layers, which are typically electrically insulating protectivelayers, disposed on at least a portion of the sensor apparatus (e.g.covering the analyte modulating layer). Acceptable polymer coatings foruse as the insulating protective cover layer can include, but are notlimited to, non-toxic biocompatible polymers such as silicone compounds,polyimides, biocompatible solder masks, epoxy acrylate copolymers, orthe like. A preferred cover layer comprises spun on silicone. Typicallythe cover layer further includes an aperture that exposes at least aportion of a sensor layer (e.g. analyte modulating layer) to a solutioncomprising the analyte to be sensed.

The analyte sensors described herein can be polarized cathodically todetect, for example, changes in current at the working cathode thatresult from the changes in oxygen concentration proximal to the workingcathode that occur as glucose interacts with glucose oxidase.Alternatively, the analyte sensors described herein can be polarizedanodically to detect for example, changes in current at the workinganode that result from the changes in hydrogen peroxide concentrationproximal to the working anode that occur as glucose interacts withglucose oxidase. In typical embodiments of the invention, the current atthe working electrode(s) are compared to the current at a referenceelectrode(s) (a control), with the differences between thesemeasurements providing a value that can then be correlated to theconcentration of the analyte being measured. Analyte sensor designs thatobtain a current value by obtaining a measurement from a comparison ofthe currents at these dual electrodes are commonly termed, for example,dual oxygen sensors.

In some embodiments of the invention, the analyte sensor apparatus isdesigned to function via anodic polarization such that the alteration incurrent is detected at the anodic working electrode in the conductivelayer of the analyte sensor apparatus. Structural design features thatcan be associated with anodic polarization include a sensorconfiguration comprising a working electrode that is an anode, a counterelectrode that is a cathode and a reference electrode. The appropriateanalyte sensing layer is then selectively disposed on the appropriateportion of the surface of the anode within this design configuration.Optionally, this anodic polarization structural design includes anodes,cathodes and/or working electrodes having different sized surface areas.For example, this structural design includes features where the workingelectrode (anode) and/or the coated surface of the working electrode islarger than the counter electrode (cathode) and/or the coated surface ofthe counter electrode. In this context, the alteration in current thatcan be detected at the anodic working electrode is then correlated withthe concentration of the analyte.

In certain illustrative examples of this embodiment of the invention,the working electrode is measuring and utilizing hydrogen peroxide inthe oxidation reaction, wherein hydrogen peroxide is produced by anenzyme such as glucose oxidase or lactate oxidase upon reaction withglucose or lactate, respectively. Such embodiments of the inventionrelating to electrochemical glucose and/or lactate sensors having suchhydrogen peroxide recycling capabilities are desirable because therecycling of this molecule reduces the amount of hydrogen peroxide thatcan escape from the sensor into the environment in which it is placed.In this context, implantable sensors that are designed to reduce therelease of tissue irritants such as hydrogen peroxide will have improvedbiocompatibility profiles. Optionally, the analyte modulating layer(e.g. a glucose limiting layer) can include compositions that inhibitthe diffusion of hydrogen peroxide out into the environment in which thesensor is placed. Consequently, such embodiments of the inventionimprove the biocompatibility of sensors that incorporate enzymes thatproduce hydrogen peroxide by incorporating hydrogen peroxide recyclingelements disclosed herein.

Certain embodiments of the analyte sensors of the invention thatcomprise a base layer, a conductive layer, an analyte sensing layer, anoptional protein layer, an adhesion promoting layer, and analytemodulating layer and a cover layer exhibit a number of advantageousproperties. For example, in sensors that are structured to function viaanodic polarization versus those structured to function via cathodicpolarization, differences in the electrochemical reactions in theanalyte sensing layer as well as at the electrode surface generateand/or consume different chemical entities, thereby altering thechemical environment in which the various sensor elements function indifferent polarities. In this context, the sensor structure disclosedherein provides a surprisingly versatile device that is shown tofunction with an unexpected degree of stability under a variety ofdifferent chemical and/or electrochemical conditions.

In certain embodiments of the invention disclosed herein (e.g., thosehaving hydrogen peroxide recycling capabilities) the sensor layer has aplurality of electrodes including a working electrode (e.g. an anode)and a counter electrode (e.g. a cathode), both of which are coated witha analyte sensing layer comprising an enzyme such as glucose oxidase orlactate oxidase. Such sensor designs have an enhanced sensitivity.Without being bound by a specific theory, these properties may resultfrom the enhanced oxidation of hydrogen peroxide at the surface of aworking or a counter electrode, which produces additional oxygen thatcan be utilized in the glucose sensing reaction. Therefore thisrecycling effect may reduce the oxygen dependent limitations of certainsensor embodiments disclosed herein. Moreover, this design may result ina sensor having a working electrode that can readily reduce availablehydrogen peroxide and consequently has a lower electrode potential.Sensors designed to function with lower electrode potentials arepreferred because high electrode potentials in sensors of this type canresult in a gas producing hydrolysis reaction, which can destabilize thesensors (due to the disruption of sensor layers from gas bubblesproduced by hydrolysis reactions). In addition, in sensor embodimentswherein the counter electrode is coated with a very thin layer of ananalyte sensing layer comprising an enzyme such as glucose oxidase orlactate oxidase, the hydrogen peroxide generated in the enzymaticreaction is very close to the reactive surface of the counter electrode.This can increase the overall efficiency of the sensor in a manner thatallows for the production of compact sensor designs which include forexample, counter electrodes with smaller reactive surfaces.

A specific illustrative example of an analyte sensor apparatus forimplantation within a mammal is a peroxide sensor having a first, baselayer, typically made from a ceramic such as alumina. A subsequent layerdisposed upon the base layer is conductive layer having a plurality ofelectrodes, including an anodic working electrode and a referenceelectrode. A subsequent layer disposed on the conductive layer is ananalyte sensing layer that includes crosslinked glucose oxidase, whichsenses glucose and consequently generates hydrogen peroxide. In thepresence of this hydrogen peroxide, the anodic working electrodeexperiences a measurable increase in current as the hydrogen peroxidegenerated contacts this anode in the conductive layer and is oxidized.The reference electrode serves as a control and is physically isolatedfrom the working electrode and the hydrogen peroxide generated. Thisanalyte sensing layer is preferably less than 1, 0.5, 0.25 or 0.1microns in thickness and comprises a mixture of crosslinked human serumalbumin in a substantially fixed ratio with the crosslinked glucoseoxidase, with the glucose oxidase and the human serum albumin beingdistributed in a substantially uniform manner throughout the sensorlayer. A subsequent layer disposed on the sensor layer is a proteinlayer comprising crosslinked human serum albumin. A subsequent layerdisposed on the protein layer is an adhesion promoting layer, whichpromotes the adhesion between the analyte sensing layer and/or theprotein layer and an analyte modulating layer disposed upon theselayers. This adhesion promoting layer comprises a silane composition. Asubsequent layer disposed on the adhesion promoting layer is the analytemodulating layer in the form of a hydrophilic glucose limiting membranecomprising PDMS. A subsequent layer is a cover layer, typically composedof silicone, which is disposed on at least a portion of the analytemodulating layer, wherein the cover layer further includes an aperturethat exposes at least a portion of the analyte modulating layer to theexternal glucose containing environment so that the glucose can accessthe analyte sensing layer on the working electrode.

This peroxide sensor apparatus functions via anodic polarization suchthat the hydrogen peroxide signal that is generated by glucose diffusingthrough the analyte modulating layer and then reacts with the glucoseoxidase in the analyte sensing layer creates a detectable change in thecurrent at the anodic working electrode in the conductive layer of thesensor that can be measured by an amperometer. This change in thecurrent at the anodic working electrode can then be correlated with theconcentration of glucose in the external environment. Consequently, asensor of this design can act as a peroxide based glucose sensor.

Hydrophilic Coating

In some embodiments, the sensor includes a hydrophilic coating. Thecoating applied to a sensor embodiment of the invention includes ahydrophilic polymer. Examples of hydrophilic materials include, but arenot limited to, polyureas, polyamides, polyurethanes, acrylates,polyesters, polyethylene oxide (PEO) or cross-linked PEO. A preferredhydrophilic material for use in accordance with the invention is a PEOcontaining polyurethane or PEO containing polyurea. PEOs can becross-linked by a variety of methods known in the art, including via theuse of a gas plasma, or ionizing radiation such as electron or gammasources, for example.

It is desirable to obtain a very hydrophilic membrane at the interfacebetween the sensor and the biological environment. Accordingly, thecoating is at least sufficiently hydrophilic to achieve swelling and gelformation. Preferably, the coating is sufficiently hydrophilic that,upon contact with a wet environment, it achieves a swell volume of atleast about two, three, four or five times the thickness of the coatingin a dry environment. Preferably, the coating is sufficientlyhydrophilic, oxygen permeable and/or optically transparent so as to notchange the overall analyte sensing capability of the sensor. Ideally,the coating achieves the maximal swell volume that does not disruptadhesion with the underlying material.

Preferred hydrophilic materials include, but are not limited to, PEOcontaining polyurethanes, such as HydroMed™ TPH-D640 (available fromCardioTech International). Such a polyurethane is suitable forapplication over the top of polymeric coatings currently in use withglucose sensors, such as glucose limiting polymer (GLP; MiniMed, Inc.,Northridge, Calif.). In such applications, the hydrophilic materialpreferably does not limit glucose and is readily incorporated into thesensor production process.

The hydrophilic material is applied by conventional means, includingdip-coating or spraying the coating onto the sensor surface, e.g., overthe GLP or optochemical sensing polymer. Typically, dip-coating is usedto coat only the distal end of the sensor. The preferred polymer doesnot impede the diffusion of glucose, is soluble in a volatile organicsolvent, such as tetrahydrofuran (THF) or isopropyl alcohol or mixturethereof (e.g., 25/75), that is suitable for spraying without disruptingthe original surface. Damage to the underlying surface could affect themass transfer properties of the underlying material and result inerratic sensor behavior. Alternatively, the hydrophilic material can beapplied by painting or other means known in the art.

Therapeutic Agents

A medicinal or therapeutic agent can be incorporated into thehydrophilic material for the coating of the sensor. The agent isselected in accordance with the desired effect. For example, theobjective may be to prevent or minimize inflammation or microbialinfection. Examples of therapeutic agents include, but are not limitedto, anti-inflammatory, anti-bacterial, anti-viral, anti-coagulant, anddisinfecting agents, such as dexamethasone, cefazolin, and benzalkoniumchloride, and/or a growth factor. In some embodiments, the therapeuticagent may be an anti-proliferative agent that kills growing cells suchas microbial organisms or reactive cells. In a preferred embodiment, thehydrophilic coating includes an anti-inflammatory agent, such asdexamethasone or a salt thereof. Suitable water-soluble salts ofdexamethasone include, but are not limited to, the sodium phosphate oracetate salts. Dexamethasone serves to reduce inflammation and also todeactivate macrophages, which allows for enhanced sensor performance.

Polymer Layer

In a preferred embodiment, the polymer layer comprises polyurea (see,e.g., U.S. Pat. Nos. 5,777,060 and 5,786,439). Examples of a suitablepolymer layer for a biosensor include, but are not limited to, glucoselimiting polymer (GLP; Medtronic MiniMed, Inc., Northridge, Calif.).Other formulations of the polymer layer can be selected in accordancewith the desired use. For example, U.S. Pat. Nos. 5,777,060 and5,786,439 describe coatings suitable for use with biosensors,particularly for use with glucose oxidase and glucose detection. Thesecoatings share features in common with GLP, and can be adapted for usewith other types of sensors.

Assembly Means

The assembly means 14 couples the apparatus to a venous flow device 10in a manner that brings the sensor 16 into contact with blood. Theassembly means 14 has a sensor end 20 and an exterior face. The sensorend 20 refers to the portion of surface of the assembly means 14 that isenclosed when the assembly means 14 is coupled to a venous flow device10. The sensor 16 is affixed to the sensor end 20 of the assembly means14 and is positioned within the venous flow device 10 upon coupling ofthe assembly means 14 to a venous flow device 10.

In a typical embodiment, the assembly means 14 comprises a lure lockconnector 18, of either the fixed or rotating variety. Variations on alure lock 18, or a custom cap or housing can serve as an assembly means14, providing a means for introducing the sensor 16 into the area ofblood flow while protecting the integrity of the venous flow. Theassembly means 14 can be designed to clip into place for secure andaccurate positioning. A clip 70 can be used to attach and/or release theapparatus 14 to and from the venous flow device 10.

The assembly means 14 can be configured in a variety of ways, dependingon the features of the venous flow device 10 to which it will becoupled, and on the desired positioning of the sensor 16 within thevenous flow device 10. For example, it may be desirable to orient thesensor electrodes perpendicular, parallel, or at an angle with respectto the direction of blood flow. The assembly means 14 can includefeatures that enhance security of the coupling to avoid inadvertentdisconnection of the apparatus 14 from the venous flow device 10, or toavoid disruption of sensor function. A variety of exemplary embodimentsof the assembly means 14 are depicted in FIGS. 1A-7C and 9A-10C.

In some embodiments of the apparatus, the assembly means 14 furthercomprises an alignment means 46 adapted to guide insertion of the sensor16 into a venous flow device 10. For example, the alignment means 46 cancomprise a needle having a lumen, or other piercing device. The piercingdevice 50 can be fixed or removable, and optionally, includes a slot 82or other means to allow removal of the piercing device 50 withoutremoving the sensor 16. The sensor shape can also be modified tofacilitate removal of the piercing device 50 without disturbing thesensor 16 position.

Venous Flow Device

In some embodiments, the apparatus further comprises a venous flowdevice 10 coupled to the assembly means 14. The venous flow device 10has a lumen 22 through which blood flows, and the sensor 16 is suspendedwithin the lumen 22 of the venous flow device 10. The venous flow device10 can be an intravenous catheter 90, such as a peripheral catheter,central catheter, or peripherally-inserted central catheter. In someembodiments, the venous flow device 10 comprises an external blood loop,such as is used in extra-corporeal membrane oxygenation or hemodialysis.The venous flow device 10 can have one or more lumens 22. The lumens canbe in a coaxial or side-by-side arrangement. Optionally, an opening isprovided between the lumens. An inter-lumenal opening can permit theintroduction of a medication, such as an anti-coagulant, into the areain which the sensor is suspended. Placement of the opening or openingscan be designed to direct the medication or other agent to a particularportion or region of the sensor. In one embodiment, the assembly means14 further comprises a side port 92 that provides a passage extendingfrom the exterior of the assembly means to the lumen 22 of the venousflow device 10.

In some embodiments, the venous flow device 10 further comprises aseptum 60 adapted to receive injections. For use with an external bloodloop, the septum 60 can be affixed to a T-connector 12, for example, sothat a sensor apparatus can be introduced into the external blood loopthrough the septum 60. In another embodiment, the external blood loopfurther comprises a cross connector 40 adapted to receive injectionsfrom opposing sides of the external blood loop, or to receive anassembly means 14 at one side and an alignment means 46 at the opposingside, which serves to guide the sensor 16 into place.

The apparatus can further comprise a medication delivery system, whereinthe medication delivery system comprises means for infusing a medicationinto the venous flow device. In addition, the apparatus can include afeedback loop, wherein an output from the sensor is communicated to themedication delivery system. In such a closed loop system, sensor outputcan control infusion of medication, such as insulin and/or glucose, orother desired medication whose dosage would be adjusted on the basis ofsensor-gathered information.

Monitors & Other Devices

In some embodiments, the sensor is operatively coupled to a monitor orother device. The coupling can be direct or telemetric, and facilitatescontinuous or regular monitoring of the subject's analyte levels. Forexample, in a hospital setting, the apparatus can be used to monitor apatient's glucose or other analyte level from a remote location, such asa nursing station.

In such an embodiment, the sensor communicates with a user interface aspart of a sensing system. The sensing system may also include anauxiliary device. Examples of a user interface include, but are notlimited to, a handheld device, such as a handheld computer, personaldata assistant (PDA), telephone, remote control, and the like. Arepresentative auxiliary device is a patient monitor. Representativesensing systems are described in U.S. patent application Ser. No.10/899,623, filed Jul. 27, 2004, and entitled, “Sensing System withAuxiliary Display”.

The sensor can be wired to a user interface, which is wired to anauxiliary device, such as a patient monitor. The sensor is typically areal-time sensor. The user interface may provide power to the sensorand/or the monitor may provide power to the sensor. Alternatively, themonitor recharges the user interface, which powers the sensor. The userinterface may be detached from the patient monitor while the sensor isstill powered and working. The user interface may transmit datawirelessly to the monitor. Alternatively, the glucose sensor may bewired to both a user interface and a patient monitor. The sensor may bepowered by the user interface, monitor, or both.

The sensor electronics may include factory supplied reference values fora sensor. The factory supplied reference values may be stored in anonvolatile memory, which can also be placed into a user interface forcalibrating sensor signals. Reference values can be communicated to thesensor electronics or user interface directly from a blood glucosemeter. The reference values can be downloaded to a personal computer ormanually entered into a personal computer and then uploaded to the userinterface and optionally sent to the sensor electronics. The referencevalues can be manually entered into the user interface and optionallysent to the sensor electronics.

The sensor electronics may include one or more of a sensor power supply,a regulator, a signal processor, a measurement processor, a measurementmemory and a reference memory. The user interface may include one ormore of a user interface power supply, a user interface processor, areference memory, a measurement processor, a measurement memory, asignal processor, a regulator, and a mechanism for receiving data froman input device and/or sending data to an output device. Either or bothof the user interface and sensor electronics can include a wirelesscommunication mechanism.

FIG. 11A is a block diagram of a characteristic monitoring system 100that can be used in accordance with an embodiment of the presentinvention. The characteristic monitoring system 100 generally includes asensor set 102 that employs a sensor (as part of the apparatus of theinvention) that produces a signal that corresponds to a measuredcharacteristic of the user, such as a blood glucose level. The sensorset 102 communicates these signals to a characteristic monitor 104 thatis designed to interpret these signals to produce a characteristicreading or value for the user, i.e. a measurement of the characteristic.The sensor signals enter the monitor 104 through a sensor input 106 andthrough the sensor input 106 the signals are conveyed to a processor108. The processor 108 determines and manipulates the sensor readingswithin the monitor 104. The characteristic monitor 104 can provideadditional functions that will aid in the treatment regime to which thecharacteristic reading applies. For example, the monitor may trackmeals, exercise and other activities that affect the treatment ofdiabetes. These additional functions can be combined with or independentfrom the characteristic readings determined by the monitor 104. Monitorsof the invention have a number of embodiments and can for example becoupled to an infusion pump that can further provide a medication to auser.

Other components of the monitor 104 support the processor 108 inperforming functions. A memory 110 is used to store data andinstructions used by the processor 108. A data entry device 112 such asa keypad is used to receive direct input from the user and a display 114such as a liquid crystal display (LCD), or the like, is used to relateinformation to the user. In addition, the monitor 104 includes a dataport 116, such as a digital input/output (I/O) port.

The data port 116 can be used for the monitor 104 to communicate with acomputer 118. To facilitate communication, the monitor 104 may interfacewith the computer 118 through a communication station 120 that can serveas a docking station for the monitor 104, for example. In someembodiments, the data port 116 within the monitor 104 can be directlyconnected to the computer 118. Through the communication link, data maybe downloaded from the monitor 104, such as stored characteristicreadings, settings, programs and other information related to themonitor's function. Thus, advanced analysis can be performed on thecomputer 118, freeing memory 110 within the monitor 104. Data such ascharacteristic readings, settings and programs can also be downloaded tothe monitor 104. In this way, the monitor 104 can be convenientlyreprogrammed without requiring tedious manual entry by the user.

FIG. 11B is a block diagram of a telemetered characteristic monitoringsystem embodiment of the invention. In this system embodiment 200, thesensor input 106 of the monitor 104 is a wireless receiver, such as aradio frequency (RF) receiver. The sensor set 102 provides a signal viawired link to a telemetered monitor transmitter 202, where the signal isinterpreted and converted to an RF signal. The wireless receiver sensorinput 106 of the monitor 104 converts the signal to data understandableto the monitor processor. With some advantages, the telemeteredcharacteristic monitoring system can perform any or all the functions ofthe characteristic monitoring system of FIG. 11A.

A characteristic monitoring system 100, in accordance with a preferredembodiment of the present invention, includes a sensor set 102 andcharacteristic monitor device 104. The sensor set 102 generally utilizesan electrode-type sensor. However, in alternative embodiments, thesystem can use other types of sensors, such as electrically basedsensors, chemically based sensors, optically based sensors, or the like.The sensor set 102 is connected to the monitor device 104 and provides asignal based upon the monitored characteristic (e.g., blood glucose).The characteristic monitor device 104 utilizes the received signal todetermine the characteristic reading or value (e.g., a blood glucoselevel).

The telemetered characteristic monitor transmitter 202 generallyincludes the capability to transmit data. In alternative embodiments,the telemetered characteristic monitor transmitter 202 can include areceiver, or the like, to facilitate two-way communication between thesensor set 102 and the characteristic monitor 104. In alternativeembodiments, the characteristic monitor 104 can be replaced with a datareceiver, storage and/or transmitting device for later processing of thetransmitted data or programming of the telemetered characteristicmonitor transmitter 202. In addition, a relay or repeater can be usedwith a telemetered characteristic monitor transmitter 202 and acharacteristic monitor 104 to increase the distance that the telemeteredcharacteristic monitor transmitter 202 can be used with thecharacteristic monitor 104.

For example, a relay can be used to provide information to parents ofchildren using the telemetered characteristic monitor transmitter 202and the sensor set 102 from a distance. In a related embodiment, a relaycan be used to provide information to medical professional and/orrelated caregiver regarding the physiological status of a user (e.g. ahypoglycemic event) in a situation where that event has not beenacknowledged and/or addressed by the user within a specific timeparameter (e.g. 15-45 minutes). In one illustrative embodiment, aphysiological characteristic monitoring system includes a relay thatautomatically dials a predetermined telephone number as part of anotification scheme for an event that has not been acknowledged and/oraddressed by the user. In further embodiments, the relay can include thecapability to sound an alarm. In addition, the relay can be capable ofproviding telemetered characteristic monitor transmitter 202 data fromthe sensor set 102, as well as other data, to a remotely locatedindividual via a modem connected to the relay for display on a monitor,pager or the like. The data can also be downloaded through thecommunication station 120 to a remotely located computer 118 such as aPC, laptop, or the like, over communication lines, by modem, wired orwireless connection. Wireless communication can include for example thereception of emitted radiation signals as occurs with the transmissionof signals via RF telemetry, infrared transmissions, opticaltransmission, sonic and ultrasonic transmissions and the like. Asdisclosed herein, some embodiments of the invention can omit thecommunication station 120 and use a direct modem or wireless connectionto the computer 118. In further embodiments, the telemeteredcharacteristic monitor transmitter 202 transmits to an RF programmer,which acts as a relay, or shuttle, for data transmission between thesensor set 102 and a PC, laptop, communication station 118, a dataprocessor, or the like. In further alternatives, the telemeteredcharacteristic monitor transmitter 202 can transmit an alarm to aremotely located device, such as a communication station 118, modem orthe like to summon help.

In addition, further embodiments can include the capability forsimultaneous monitoring of multiple sensors and/or include a sensor formultiple measurements.

The characteristic monitor device 104 receives characteristicinformation, such as glucose data or the like, from the sensor set 102and displays and/or logs the received glucose readings. Logged data canbe downloaded from the characteristic monitor 104 to a PC, laptop, orthe like, for detailed data analysis. In further embodiments, thecharacteristic monitoring system 100, 200 can be used in a hospitalenvironment, or the like. For example, in a hospital environment, sensorinformation can be relayed to monitors in the patient room, to thenurses station, to the patients electronic medical records, and/or to apump system which will use the information for closed-loop control ofblood sugar levels. Still further embodiments of the present inventioncan include one or more buttons to record data and events for lateranalysis, correlation, or the like. Further buttons can include a sensoron/off button to conserve power and to assist in initializing the sensorset 102. The characteristic monitoring system 200 can also be employedwith other medical devices to combine other patient data through acommon data network system.

Further embodiments of the sensor set 102 can monitor the temperature ofthe sensor set 102, which can then be used to improve the calibration ofthe sensor. For example, for a glucose sensor, the enzyme reactionactivity may have a known temperature coefficient. The relationshipbetween temperature and enzyme activity can be used to adjust the sensorvalues to more accurately reflect the actual characteristic levels. Inaddition to temperature measurements, the oxygen saturation level can bedetermined by measuring signals from the various electrodes of thesensor set 102. Once obtained, the oxygen saturation level can be usedin calibration of the sensor set 102 due to changes in the oxygensaturation levels and its effects on the chemical reactions in thesensor set 102. For example, as the oxygen level goes lower, the sensorsensitivity can be lowered. In alternative embodiments, temperaturemeasurements can be used in conjunction with other readings to determinethe required sensor calibration.

In preferred embodiments, the sensor set 102 facilitates accurateplacement of a flexible thin film electrochemical sensor of the typeused for monitoring specific blood parameters representative of a user'scondition. Preferably, the sensor monitors glucose levels in the body,and can be used in conjunction with automated or semi-automatedmedication infusion devices of the external or implantable type asdescribed in U.S. Pat. Nos. 4,562,751; 4,678,408; 4,685,903 or 4,573,994(which are incorporated herein by reference), to control delivery ofinsulin to a diabetic patient. In addition, the monitor characteristicmonitor 104 may typically be integrated into such a medication infusiondevice so that medication delivery and monitoring are convenientlyprovided within a single device.

Embodiments of the flexible electrochemical sensor can be constructed inaccordance with thin film mask techniques to include elongated thin filmconductors embedded or encased between layers of a selected insulativematerial, such as polyimide film or sheet, and membranes. The sensorelectrodes at a tip end of the sensing portion are exposed through oneof the insulative layers for direct contact with patient blood or otherbody fluids, when the sensing portion (or active portion) of the sensoris subcutaneously placed at an insertion site. The sensing portion isjoined to a connection portion that terminates in conductive contactpads, or the like, which are also exposed through one of the insulativelayers. In alternative embodiments, other types of implantable sensors,such as chemical based, optical based, or the like, can be used. Furtherdescription of flexible thin film sensors of this general type are befound in U.S. Pat. No. 5,391,250, entitled “METHOD OF FABRICATING THINFILM SENSORS”, which is herein incorporated by reference. The connectionportion can be conveniently connected electrically to the monitor 104 ora telemetered characteristic monitor transmitter 202 by a connectorblock (or the like) as shown and described in U.S. Pat. No. 5,482,473,entitled “FLEX CIRCUIT CONNECTOR”, which is also herein incorporated byreference. Thus, in accordance with embodiments of the presentinvention, subcutaneous sensor sets 102 are configured or formed to workwith either a wired or a wireless characteristic monitoring system 100,200.

Methods

The invention additionally provides a method of introducing a sensorinto the circulating blood of a subject. The method comprises contactinga venous flow device with the circulating blood of the subject andintroducing an apparatus of the invention into the venous flow device.The sensor contacts the circulating blood of the subject as the bloodflows through the venous flow device. In one embodiment, the venous flowdevice comprises an external blood loop having a port adapted to receivethe apparatus. Optionally, the external blood loop further comprises asecond port adapted to receive an alignment means. The method canfurther comprise introducing an alignment means into the external bloodloop from a side opposing the port adapted to receive the apparatusprior to introducing the apparatus.

In one embodiment, the method further comprises introducing an alignmentmeans into the port prior to or simultaneously with introduction of theapparatus. The alignment means can be removed following introduction ofthe apparatus. Alternatively, the venous flow device can be a catheter.

In addition, embodiments of the invention provide a method formonitoring or detecting a biological substance in a subject. Thebiological substance may be glucose, lactate, amino acids or otheranalyte of interest. The method includes contacting an apparatus of theinvention with blood or other tissue of the subject, and detecting thepresence of the substance or analyte via the sensor. The method isparticularly suited for subjects requiring repeated and/or continuousmonitoring of an analyte, such as glucose for people with diabetes.

Also provided are methods for producing a sensor and apparatus asdescribed herein. Such methods are readily accomplished using artaccepted techniques. For example those of skill in the art can producean illustrative embodiment of the method by generating an elongatedconductive material having a protrudent end, the protrudent endcomprising an electrode that detects the presence of an analyte;affixing a substrate to the conductive material; and coupling theseelements to a support having an external surface, a proximal end, and adistal end; wherein the conductive material is positioned on the supportand the protrudent end of the conductive material protrudes beyond thedistal end of the support.

The foregoing description of preferred embodiments of the invention hasbeen presented for the purposes of illustration and description. It isnot intended to be exhaustive or to limit the invention to a preciseform disclosed. Many modifications and variations are possible in lightof the above teaching. It is intended that the scope of the invention belimited not by this detailed description, but rather by the claimsappended hereto.

What is claimed is:
 1. A method of detecting an analyte in a tissue of asubject comprising contacting the tissue of the subject with anapparatus comprising: an elongated conductive material having aprotrudent end, the protrudent end comprising a sensor that detects thepresence of an analyte, wherein the sensor comprises a plurality oflayers including: a base layer; a plurality of electrodes disposed onthe base layer; an analyte sensing layer disposed upon the electrode; ananalyte modulating layer disposed on the analyte sensing layer; and asupport having a proximal end and a distal end; wherein the conductivematerial is positioned on the support and the protrudent end of theconductive material comprising the sensor that detects the presence ofan analyte: (a) protrudes beyond the distal end of the support; and (b)is positioned on the support in combination with a venous flow deviceand assembly means, wherein the sensor is affixed to a sensor end of theassembly means and the assembly means is adapted for coupling with thevenous flow device.
 2. The method of claim 1 wherein: the plurality ofelectrodes disposed on the base layer include a working electrode, acounter electrode, and a reference electrode, the analyte sensing layercomprises glucose oxidase; and the analyte sensing layer is disposedupon the working electrode.
 3. The method of claim 1 wherein the supportfurther comprises an intravenous infusion catheter having a lumen and anexternal surface.
 4. The method of claim 3 wherein the protrudent end ofthe conductive material comprising the sensor that detects the presenceof an analyte is positioned on the external surface of the intravenousinfusion catheter.
 5. The method of claim 1, wherein the venous flowdevice comprises an external blood loop.
 6. The method of claim 5,wherein the external blood loop further comprises a septum adapted toreceive injections.
 7. The method of claim 1, wherein the sensorcomprises a hydrophilic coating, wherein the coating swells and forms agel upon contact with a wet environment.
 8. The method of claim 7,wherein the coating achieves a swell volume upon contact with a wetenvironment that is of at least two times the thickness of the coatingin a dry environment.
 9. The method of claim 2, further comprising: acover layer disposed on the analyte modulating layer and having anaperture, wherein the aperture is formed in the cover layer so as toexpose the working electrode disposed at the distal end of the supportto the tissue of the subject.
 10. The method of claim 9, wherein thereference electrode is disposed on the support at a location relative tothe aperture that is selected to avoid reference electrode exposure tothe tissue of the subject.
 11. The method of claim 1, wherein the sensorexhibits a flexibility that is sufficient to permit threading of thesensor through a venous flow device or a blood vessel.
 12. The method ofclaim 1, further comprising an external coating disposed on the sensor,wherein the external coating comprises an anticoagulant,anti-inflammatory or antimicrobial agent.
 13. A method of detecting ananalyte in a tissue of a subject comprising: (i) contacting a venousflow device with a tissue of the subject; and (ii) coupling with thevenous flow device an apparatus comprising: an elongated conductivematerial having a protrudent end, the protrudent end comprising a sensorthat detects the presence of an analyte, wherein the sensor comprises aplurality of layers including: a base layer; an electrode disposed onthe base layer; an analyte sensing layer; and a support having aproximal end and a distal end; wherein the conductive material ispositioned on the support and the protrudent end of the conductivematerial comprising the sensor that detects the presence of an analyte:(a) protrudes beyond the distal end of the support; and (b) ispositioned on the support in combination with the venous flow device andan assembly means, wherein the sensor is affixed to a sensor end of theassembly means and the assembly means is adapted for coupling with thevenous flow device.
 14. The method of claim 13 wherein the analyte isglucose, lactate or an amino acid.
 15. The method of claim 13 whereinthe tissue is circulating blood of the subject.
 16. The method of claim13 wherein the support further comprises an intravenous infusioncatheter having a lumen and an external surface.
 17. The method of claim16 wherein the protrudent end of the conductive material comprising thesensor that detects the presence of an analyte is positioned on theexternal surface of the intravenous infusion catheter.
 18. The method ofclaim 13, wherein the venous flow device comprises an external bloodloop.
 19. The method of claim 18, wherein the external blood loopfurther comprises a port adapted to receive an alignment means.
 20. Themethod of claim 13, further comprising introducing an alignment meansinto the external blood loop from a side opposing the assembly meansprior to coupling the apparatus with the venous flow device.